Interbacterial signaling, commonly referred to as quorum sensing (QS) enables bacteria to coordinate their behavior in order to function as a group. Using diffusible chemical signals to initiate a concerted population response depends on the population reaching a threshold number or “quorum”. Most microbes require a “quorate population” to manifest an infection in its target host. This bacterial intercellular communication system relies on the production and release of QS molecules that control the expression of multiple target genes which play a pivotal role in virulence and pathogenicity in the host. The most intensively investigated QS signal molecules are acyl-homoserine lactones (AHLs) synthesized by many quorum-sensing, secreting bacteria. AHLs are used to regulate infection, virulence and survival functions. Different bacterial species can produce different AHLs. The basic structure of AHLs consists of a homoserine lactone ring adjoined with an N-acyl chain, ranging in length from 4 or 14 carbons, which may be saturated or unsaturated and may or may not contain a hydroxy- or oxo-group at the 3-carbon position.
To date, AHL-dependent QS circuits have been identified in a wide range of gram-negative bacteria, one example of which is Pseudomonas aeruginosa, where the QS circuits regulate various functions to survive in the host. The severity and diversity of infections caused by P. aeruginosa, is in part due to its ability to produce a plethora of environment-dependent virulence factors but also due to its recalcitrance to antibiotic treatment when growing in biofilm.
The accepted clinical intervention strategy in bacterial infections is treatment with antibiotics. However, currently prescribed small molecule antibiotics have limitations, especially in advanced infectious states when systemic application cannot provide the required local dose of antibiotics necessary for effective bactericidal action due to compromised half-life of the drug. The efficacy of the antibiotic depends on factors such as selective toxicity, bioavailability of the drug and penetration into the target bacteria. Some very effective antibacterial compounds are unacceptable for human use as they are toxic at their prescribed doses, chiefly due to the fact that current delivery regimens are systemic, thus requiring a whole body dosage to achieve necessary local concentrations. There exists an ongoing need, therefore, for effective treatment of bacterial infections without the disadvantages resulting from traditional systemic application of antibiotics.